Psychoses are a group of behavioral, judgment and perception disorders with an emotional or organic origin in which the person loses touch with reality. Their durations, characteristics and treatments all differ. They are usually chronic disorders and can occur with a severe and very dysfunctional symptomatology.
Schizophrenia is a mental disorder affecting 1% of the world population and is characterized by a loss of judgment of reality and a personality disorder, probably due to a biochemical or microstructural brain defect that has not yet been well determined. There is a wide variety of symptoms indicative of schizophrenia, including thought disorders, hallucinations, abnormal movements and amotivational behavior. None of these symptoms is pathognomic of the disorder, which makes diagnosis difficult. It has an unknown cause although it is though that several factors are involved in its onset, including genetic heritage, disorders in cell population migration during embryonic development, drug abuse and environmental stress. It is a chronic disease but improves with treatment, especially with drugs.
As in many mental disorders, the diagnosis of schizophrenia is based on the behavior of the person being evaluated. There is a list of criteria that a person must meet in order to be diagnosed with the disorder and these criteria depend on the presence and duration of certain signs and symptoms.
The most widely used criteria to diagnose schizophrenia are set forth in the DSM, Diagnostic and statistical manual of mental disorders of the American Psychiatry Association and the World Health Organisation: International Statistical Classification of Illnesses and related Health Problems (ICD)]. The most recent versions are ICD-10 and DSM-IV-TR.
In order to be diagnosed with schizophrenia a person must exhibit a series of characteristic symptoms for several months. There are no biological markers with a diagnostic, at the onset thereof, or prognostic value for this disorder. This shortcoming is very limiting because various psychiatric disorders start with similar symptoms. This is why it is very difficult to initially distinguish schizophrenia from other mental disorders, such as bipolar disorder or manic-depressive disorder, major depression or other nonspecified psychoses. People whose symptoms cannot be clearly classified sometimes receive the diagnosis of “schizoaffective disorder”.
In addition, bipolar disorder (also referred to as type I bipolar disorder) occurs with episodes of mania and depression and may also present psychosis at the onset thereof. This disorder affects about 2% of the world population and its correct diagnosis is done according to the criteria described in ICD-10 and DSM-IV-TR; however, said diagnosis may take up to several years after the first episode. Once bipolar disorder is diagnosed it can be effectively treated.
Until now no biological markers have been described which allow a differential diagnosis of severe psychoses (schizophrenia and bipolar disorder) and of other nonspecified psychoses. The diagnosis of such disorders at the onset of symptoms is extremely important for establishing a suitable treatment that can improve the evolution of the disorder in the long term for the patients.
Specifically, biological markers of the possible evolution of the psychosis have not been identified [Freedman R., 2005. Early biomarkers of psychosis. Dialogues Clin Neurosci. 7:17-29]. This could be because of the many complex underlying factors of schizophrenia, bipolar disorder and other psychoses. Although genotypes and phenotypes associated with these disorders have been described, some of which become apparent at early ages, they have little predictive value.
In linkage and association studies, it has been found that chromosomal regions 1q, 5p, 5q, 6p, 6q, 8p, 10p, 13q, 15q and 22q contain schizophrenia risk genes which could not always be replicated in all the studied populations [Berry N. et al., 2003. Molecular genetics of schizophrenia: a critical review. J Psychiatry Neurosci. 28:415-429]. In addition, neuregulin gene 1 (NRG1) is perhaps the gene that is most clearly associated with schizophrenia; however levels of this neuregulin cannot be detected in blood, and its genetic variants and polymorphisms are not well determined [Corfas G. et al., 2004. Neuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia. Nat Neurosci. 7:575-580].
As regards bipolar disorder, a number of genetic studies have been conducted which have been useful in establishing several loci associated to this disorder, including 4q31, 6q24 and 1p35-p36 [Schumacher J et al., 2005. Genomewide scan and fine-mapping linkage studies in four European samples with bipolar affective disorder suggest a new susceptibility locus on chromosome 1p35-p36 and provides further evidence of loci on chromosome 4q31 and 6q24. Am J Hum Genet. 77:1102-1111]. Immune system disorders which are detectable in manic episodes manic episodes in bipolar patients, however it has not been determined if these values are altered at the onset of the disorder [Liu HC et al., 2004. Immunologic variables in acute mania of bipolar disorder. J. Neuroimmunol. 150:116-122]. Disorders in the transferrin receptor have been observed in mania periods, but this parameter has not been assessed either in the first psychotic episode in these patients [Tsai SY et al., 2003. Plasma levels of soluble transferrin receptors and Clara cell protein (CC16) during bipolar mania and subsequent remission. J Psychiatr Res. 37:229-235].
It has now surprisingly been found that the brain-derived neutrophic factor or BDNF can be used as a molecular marker for the diagnosis of psychiatric disorders occurring with psychosis, e.g. schizophrenia and bipolar disorder. No diagnostic or therapeutic application of BDNF is known today.
BDNF is the most abundant neurotrophin in the brain, where it promotes growth and maintenance of intercellular junctions, is useful as a modulator of neurotransmitter signals and participates in plasticity mechanisms such as long-term potentiation and learning. Accordingly, BDNF signaling anomalies can affect neuronal differentiation and synaptic communication and thus alter brain development and function.
BDNF is the expression product of the BDNF gene, a gene induced by cortical neurons and necessary for survival of neurons of the striatum in the brain. The expression of said BDNF gene is reduced in patients suffering Alzheimer's disease and Huntington's disease. This gene seems to have some role in regulating the response to stress.
Plasma levels of BDNF in chronic schizophrenics have been studied, with different results according to the different groups of patients studied [Jockers-Scherübl M C., et al., 2004. Brain-derived neurotrophic factor serum concentrations are increased in drug-naive schizophrenic patients with chronic cannabis abuse and multiple substance abuse. Neurosci. Lett. 371, 79-83; Pirildar S., et al., 2004. Low serum levels of brain-derived neurotrophic factor in patients with schizophrenia do not elevate after antipsychotic treatment. Prog. Neuropsychopharmacol. Biol. Psychiatry. 28, 709-713; Toyooka K., et al., 2002. Decreased levels of brain-derived neurotrophic factor in serum of chronic schizophrenic patients. Psychiatr. Res. 110, 249-257]. However, said levels have not been determined in patients suffering the first psychotic episode, as described in the present invention.